THE EFFECT OF SOLUBLE AND INSOLUBLE FILLERS/BIND.ERS ON THE DISINTEGRATION AND DISSOLUTION OF DRUGS FROM DIRECTLY COMPRESSED TABLET FORMULATIONS

Transcription

1 THE EFFECT OF SOLUBLE AND INSOLUBLE FILLERS/BIND.ERS ON THE DISINTEGRATION AND DISSOLUTION OF DRUGS FROM DIRECTLY COMPRESSED TABLET FORMULATIONS A. KL YNSMITH B.Pharm Dissertation submitted in partial fulfilment of the requirements for the degree Magister Scientiae in Pharmaceutics at the Potchefstroomse Universiteit vir Christelike Hoer Onderwys Supervisor: Dr. A.F. Marais July 2002 Potchefstroom

2 TABLE OF CONTENTS - Table of contents... i Introduction, hypothesis and aim... iv Abstract... vi Uittreksel...;... viii 1. CHAPTER 1: Direct compression and formulation excipients: effect on tablet properties and drug release-a literature review Introduction Drug release and dissolution from compressed systems Direct compression: A significant advance in tablet manufacturing Effect of formulation variables and processing factors on properties of and drug release from directly compressed tablets Properties of some popular excipients used in direct compression formulations and their effect on tablet characteristics and drug release Fillers Binders Disintegrants Lubricant Hygroscopicity Solubility Effect of processing factors on tablet characteristics and drug release Mixing Compression force Conclusion CHAPTER 2: Experimental methods Materials Methods and apparat\js... 36

3 2.2.1 Mixture composition and preparation Compression of tablets...; Powder characteristics and physical properties of powder compacts Particle size analysis Powder density Crushing strength Friability Disintegration time Dissolution studies Apparatus and dissolution conditions Method Standard curve Calculations Dissolution data Dissolution parameters, DRi and AUC Statistical evaluation of the experimental data CHAPTER 3: Physical characterisation of Avicel PH 200 and Tablettose as tablet fillers Introduction Powder characteristics Physical properties of Avicel PH 200 and Tablettose tablets Conclusion CHAPTER 4: Evaluation of the effect of dry binders and disintegrants on the physical properties of Tablettose tablets Introduction Effect of binders on the physical properties of Tablettose tablets Effect of disintegrants on the physical properties of Tablettose tablets Conclusion ii

4 5. CHAPTER 5: Comparison of the dissolution profiles of a poorly watersoluble drug from directly compressed Avicel PH 200 and Tablettose formulations Introduction Comparison between drug dissolution profiles from Avicel and Tablettose tablets Evaluation o{ formulation variables on drug dissolution from Tablettose tablets... : Conclusion REFERENCES ANNEXURES Annexure A: Dissolution data of furosemide formulations in 0.1 M HCI iii

5 INTRODUCTION, HYPOTHESIS AND AIM The properties of directly compressed tablet formulations depend mainly on the physicochemical characteristics of the filler, since they often comprise more than 80% of the total tablet weight. These additives, however, do not only affect and determine the physical properties of the tablets, but also significantly affect (positively or negatively) the release and dissolution of the drug from the tablet formulation. It could therefore be assumed that significant differences between the physical properties of different fillers would result in varying physical tablet properties which could result in differences in drug release and drug dissolution patterns from these formulations. Microcrystalline cellulose (marketed as Avicel PH 200) and lactose (marketed as Tablettose ) are two compounds which are currently used as directly compressible fillers. These two fillers differ significantly in terms of their physicochemical properties. Avicel PH 200 is an insoluble filler with excellent disintegrating properties (Fox et al., 1963:260), whilst Tablettose is classified as a soluble fill~r without any disintegrating characteristics (Schmidt & Rubensdorfer, 1994:2907). Johnson et al. (1991 :469) found that soluble tablet formulations did not need a disintegrant, and stated that the efficiency of swelling disintegrants may actually be impeded in these formulations. The hypothesis however, is that these findings may not be applicable to slowly dissolving systems, such as would be the case with Tablettose formulations, and that these type of fillers would exhibit the same properties suggested for insoluble fillers without disintegrating properties. Although disintegration is not always a prerequisite for drug dissolution, this process plays a significant role in the rate and extent of dissolution, especially in the case of sparingly water-soluble drugs (like furosemide). The contribution of the disintegration process to drug dissolution can be attributed to an increase in the effective surfacearea of the drug (i.e. the surface-area exposed to or in direct contact with the surrounding aqueous medium). Disintegrants facilitate break-up of tablets, resulting in the rapid release of primary drug particles with a large surface area, which according to the general dissolution equation, is one of the main contributing factors to optimal drug dissolution (Kanig & Rudnic, 1984:51). iv

6 Most of the disintegrants employed in directly compressible tablet formulations, i.e. the so-called superdisintegrants like croscarmellose sodium (Ac-Di-Sol ), sodium starch glycolate and povidone (Kollidon CL) swell upon contact with liquid molecules, resulting in the development of a disintegrating force inside the tablet structure, which breaks interparticulate bonds and leads to subsequent drug release. It could therefore be expected that any factor which prevent contact between the disintegrant and the surrounding medium, could reduce disintegrant efficiency and ultimately decrease drug dissolution. These factors include hydrophobic constituents (drug and excipients), insoluble formulation components (especially the filler/binder) and compression force (which increases tablet density or decreases tablet porosity, thereby slowing down liquid penetration into tablets). The aim of this study was therefore to test the following hypothesis: 1. The differences in the solubility and disintegrating properties of directly compressible fillers have a significant effect on the dissolution of drugs for which dissolution is the rate-limiting step, i.e. sparingly water-soluble drugs like furosemide. 2. Formulation variables affecting contact between disintegrant particles and the surrounding medium can have a significant effect on drug dissolution. To.achieve the aim of the study the following will be undertaken: Characterisation and comparison of the physical powder properties of Avicel PH 200 and Tablettose (chosen as typical examples of insoluble, disintegrating and soluble non-disintegrating directly compressible fillers respectively). Changes to Tablettose formulations to improve certain shortcomings in the properties of tablets through the incorporation of specific excipients, like a dry binder and a disintegrant. Comparison.of the dissolution profiles of a sparingly water-soluble drug (furosemide) from basic Avicel PH 200, basic Tablettose and altered Tablettose formulations. Evaluation of the success of the addition of excipients to Tablettose formulations in terms of its effect on drug dissolution. v

7 ABSTRACT THE EFFECT OF SOLUBLE AND INSOLUBLE FILLERS/BINDERS ON THE DISINTEGRATION AND DISSOLUTION OF SPARINGLY SOLUBLE DRUGS FROM DIRECTLY COMPRESSED TABLET FORMULATIONS Although disintegration is not always a prerequisite for drug dissolution, this process plays a significant role in the rate and extent of dissolution, especially in the case of sparingly water-soluble drugs (like furosemide). Any factor that influences tablet disintegration, therefore, will influence drug dissolution. Since the filler often comprises more than 80% of the total tablet weight, it will affect tablet properties and therefore disintegration. The solubility of the filler is expected to play a major role in determining tablet disintegration. During the initial stage of the study the physical powder properties (density, particle size, flow properties and compressibility) of Tablettose (soluble) and Avicel PH 200 (insoluble) as tablet fillers were determined and compared in order to establish their inherent powder properties. Tablets from mixtures containing each filler and 0.5% w/w magnesium stearate (as lubricant) were prepared at a constant die fill volume at different compression pressures. Since Tablettose could not be tableted without a lubricant due to high friction during ejection, magnesium stearate was included in all formulations. Tablets were evaluated in terms of weight variation, crushing strength, friability and disintegration times. Tablettose produced tablets with extremely low crushing strengths and high friability compared to Avicel PH 200, which produced tablets with - acceptable physical properties. The most significant difference between the two formulations was observed in the disintegration times, with the Avicel tablets producing rapid disintegration whilst Tablettose produced slowly dissolving rather than disintegrating tablets. These results indicated shortcomings in the properties of Tablettose as directly compressible filler and suggested possible problems in terms of drug release. Following the results from the previous experiments, the effect of addition of 3.5, 5 and 7% w/w Kollidon 30 and Kollidon VA 64 as dry binder (to increase mechanical strength) and 0.5, 1 and 2% w/w Ac-Di-Sol, Kollidon CL and sodium starch vi

8 glycolate as disintegrant (to induce tablet disintegration) on the physical properties of Tablettose formulations was evaluated in order to eliminate the observed poor physical tablet properties. Although the presence of a dry binder had little effect on the crushing strength of the tablets it did increase the compression range during tableting, thereby increasing the compression force before capping occurred. Kollidon VA 64 (3.5%) proved to be the most efficient. The incorporation of a disintegrant, irrespective of the type or concentration of the disintegrant, resulted in a significant decrease in disintegration time (1 % of each disintegrant provided efficient disintegration). This was ascribed to a change from slowly dissolving tablets (with disintegration exceeding 15 minutes) to rapidly disintegrating tablets (with disintegration times less than 3 minutes). In the final stage the dissolution of furosemide (chosen as model drug representing sparingly water-soluble drugs for which dissolution is the rate-limiting step) from Avicel, Tablettose and Tablettose /Kollidon VA 64 and Ac-Di-Sol, Kollidon CL or sodium starch glycolate formulations was determined in 0.1 M HCI. Dissolution results were compared using calculated dissolution parameters, namely the initial dissolution rate (DRi) and the extent of dissolution (AUC). Dissolution from the slowly dissolving Tablettose tablets was significantly slower compared to the rapid disintegrating Avicel tablets, confirming the hypothesis that slowly dissolving (but non-disintegrating) formulations impede drug dissolution due to the small surfacearea of the drug exposed to the surrounding medium. The incorporation of Kollidon VA 64 (as dry binder) in Tablettose formulations resulted in unexpectedly high drug dissolution comparable with profiles obtained from the Avicel tablets, despite the fact that the tablets did not disintegrate. The literature provided an answer, indicating that Kollidon VA 64 increased the solubility of furosemide (Buhler, 1993:114), possibly due to the formation of a drug/excipient complex. Addition of a disintegrant to this formulation further increased drug dissolution due to rapid tablet disintegration. Once again no significant difference in drug dissolution was observed between the three disintegrants used. The dissolution results also indicate a dependency of the extent of drug dissolution (AUC) on the initial dissolution rate (DRi), indicating the importance (although not an absolute prerequisite) of establishment of rapid contact between drug particles and the surrounding medium through the incorporation of a disintegrant. vii

9 UITTREKSEL DIE EFFEK VAN OPLOSBARE EN ONOPLOSBARE VULSTOWWE OP DIE DISINTEGRASIE EN DISSOLUSIE VAN SWAK WATEROPLOSBARE GENEESMIDDELS VANUIT DIREK SAAMGEPERSDE TABLETTE Alhoewel disintegrasie nie altyd 'n voorvereiste vir dissolusie is nie, speel dit tog 'n baie belangrike rel in die tempo en mate van dissolusie, veral in die geval van swak wateroplosbare geneesmiddels (bv. furosemied). Dissolusie sat dus be"invloed word deur enige faktor wat disintegrasie be"invloed. Aangesien meer as 80% van 'n tablet gewoonlik uit die vulstof bestaan, sal die vulstof die tableteienskappe en uiteindelik eek die disintegrasie be"invloed. Dit word verwag dat die oplosbaarheid van die vulstof 'n greet invloed sal he op disintegrasie. Aan die begin van die studie is die fisiese poeier-eienskappe (digtheid, deeltjiegrootte, vloei-eienskappe en saampersbaarheid) van Tablettose (oplosbaar) en Avicet PH 200 (onoplosbaar) as vulstowwe, bepaal. Hierdie eienskappe is met mekaar vergelyk om die vulstowwe se inherente poeier-eienskappe te bepaal. Tablette is berei vanaf mengsels van elke vulstof met 0.5% m/m magnesiumstearaat as smeermiddel. Die tablette is by 'n konstante matrysvolume en by verskillende samepersingsdrukke getabletteer. Magnesiumstearaat is by alle tabletformules gevoeg omdat Tablettose nie getabletteer ken word sender 'n smeermiddel nie, a.g.v. hoe wrywing tydens uitstoting van die tablette. Tablette is geevalueer ten opsigte van massavariasie, breeksterkte, afsplyting en disintegrasietyd. Tablettose het tablette gelewer met baie lae breeksterktes en hoe afsplyting in vergelyking met Avicel PH 200. Avicel PH 200 het tablette gelewer met aanvaarbare fisiese eienskappe. Die belangrikste verskil tussen die twee vulstowwe was hulle disintegrasietye. Die Avicet tablette het vinnige disintegrasie getoon, maar die Tablettose tablette het eerder stadig opgelos as om te disintegreer. Hierdie resultate het gedui op tekortkominge in Tablettose as direksaampersbare vulstof en moontlike probleme met geneesmiddelvrystelling vanuit hierdie tablette. Na aanleiding van die laasgenoemde resultate is die effek van die byvoeging van sekere hulpstowwe op die fisiese eienskappe van Tablettose tablette ondersoek in 'n paging om die waargenome tekortkominge uit te skakel. Hierdie hulpstowwe het ingesluit Kollidon 30 en Kollidon VA 64 as droe bindmiddel (3.5, 5 en 7% m/m), en Ac-Di-Sol, Kollidon CL en natriumstyselglikolaat as disintegreermiddel (0.5, 1 en viii

10 2% m/m). Die byvoeging van die droe bindmiddel het min effek op die breeksterkte van die tablette gehad, alhoewel dit die samepersingsdruk verhoog het waarby tablette getabletteer 'kon word voor dekselvorming 'n probleem geword het. Kollidon VA 64.(3.5% m/m) was die doeltreffendste bindmiddel. Die byvoeging van 'n disintegreermiddel (ongeag die tipe of konsentrasie) het betekenisvolle vinniger disintegrasie tot gevolg gehad. 'n Konsentrasie van 1 % van enige disintegreermiddel het bevredigende disintegrasie gelewer. Hierdie afname in disintegrasietyd kon toegeskryf word aan die verandering van stadig oplosbare tablette (met disintegrasietye langer as 15 minute) na vinnig disintegrerende tablette (met disintegrasietye van minder as 3 minute). Laastens is die dissolusie van furosemied (in 0.1 M HCI), as modelgeneesmiddel vir swak wateroplosbare geneesmiddels waar dissolusie die snelheidsbepalende stap is, bepaal. Dissolusieprofiele is bepaal vii" tablette van Avicel, Tablettose en Tablettose /Kollidon VA 64 met Ac-Di-Sol, Kollidon CL of natriumstyselglikolaat. Dissolusieresultate is vergelyk in terme van twee berekende dissolusieparameters, naamlik die aanvanklike dissolusiesnelheid (DRi) en die mate van dissolusie (AUC). Dissolusie was aansienlik stadiger vanuit die stadig-oplosbare Tablettose tablette in vergelyking met die vinnig disintegrerende Avicel tablette. Hierdie stadige dissolusie vanuit Tablettose tablette bevestig die hipotese dat stadig oplosbare tablette wat nie disintegreer nie, dissolusie van geneesmiddels vertraag, as gevolg van die klein oppervlakarea van die geneesmiddel wat aan die omringende medium blootgestel is. Die byvoeging van Kollidon VA 64 (as droe bindmiddel) by Tablettose formules het gelei tot 'n onverwagse hoe dissolusie van die geneesmiddel wat vergelykbaar is met dissolusieprofiele wat vanaf Avicet tablette verkry is, ondanks die feit dat die tablette nie gedisintegreer het nie. Die rede vir hierdie verbeterde dissolusie is dat Kollidon VA 64 die oplosbaarheid van furosemied verbeter het (Buhler, 1993:114). Dit mag moontlik wees a.g.v. die vorming van 'n geneesmiddel-hulpstof kompleks. Deur die byvoeging van 'n disintegreermiddel by hierdie Kollidon -formule, is die dissolusie verder verhoog, wat toegeskryf kan word aan die vinnige disintegrasie van hierdie tablette. Weereens was daar nie 'n betekenisvolle verskil tussen die drie verskillende disintegreermiddels nie. Die dissolusieresultate het ook aangedui dat die mate van dissolusie (AUC) van die aanvanklike dissolusiesnelheid (DRi) afhanklik is. Dit is dus baie belangrik dat daar genoegsame kontak tussen die geneesmiddeldeeltjies en die omringende medium is, wat bewerkstellig word deur die teenwoordigheid van 'n effektiewe disintegreermiddel. ix

11 1. CHAPTER 1 DIRECT COMPRESSION AND FORMULATION EXCIPIENTS: EFFECT ON TABLET PROPERTIES AND DRUG RELEASE- A LITERATURE REVIEW 1.1 INTRODUCTION Since the active ingredient usually constitutes such a small percentage of the total tablet weight, the disintegration and dissolution of the tablet and thus bioavailability of the drug, depend largely on the characteristics of the excipients used in the tablet formulation. 1.2 DRUG RELEASE AND DISSOLUTION FROM COMPRESSED SYSTEMS Orally administered drugs must dissolve in the gastrointestinal fluids to assure rapid and optimum absorption into the systemic circulation. The dissolution of sparingly watersoluble and poorly water-wettable drugs in the GI-fluids is, amongst other factors, dependant on the effective surface-area of the drug, i.e. the surface area of the drug in contact with the surrounding aqueous medium in the GI-tract. These drugs exhibit extremely slow dissolution rates and incomplete dissolution due to their inherent low solubilities. The latter is further aggravated during tableting (compression) because of a significant reduction in the effective surface-area of the drug. In order to facilitate rapid and complete release or drug particles from the tablet matrix, the bonds between tablet components formed during compression must be broken. This process of tablet breakup, or better known as disintegration, is facilitated by excipients known as disintegrants (discussed in section ). Therefore, it seems valid to assume that tablet disintegration may be an important factor (play a significant role) during the absorption of drugs for which dissolution is the ratecontrolling step, and that it may well influence the eventual rate and extent of the therapeutic onset and efficiency of these drugs. The interdependency of tablet disintegration, drug dissolution and drug absorption is depicted in figure 1.1 as proposed by Wagner (1970:33). 1

12 Coarse particles Intact tablet ~ 11 ~ 0 [:;J [:;J O l Dissolution Slow dissolution Drug in bloodstream i Z-- Biological _ membrane r Fine particles Fast dissolution Drug in sol!jtion Figure 1. 1: A schematic representation of the processes preceding the appearance of a drug in the blood after oral administration of a tablet or capsule (Wagner, 1970:33). The first documented study of the dissolution process dated back more than a century (Noyes & Whitney, 1897:932). The major findings of their study can be summarised as follows: "the rate of solution of solids is mainly gove;irned by the difference in the concentration of the solid at the solid interface and its concentration in the surrounding medium" and can ~e quantified by equation 1.1. dc -=k(cs-ct) dt [1.1) Various researchers have studied, criticised and extended their work, which resulted in the general dissolution equation depicted in equation 1.2. dc - = k.a(cs-ct) dt [1.2] where dc/dt = dissolution rate, k = a dissolution rate constant, A = the effective surface area of the solid, Cs = the saturation concentration of the solid and Ct = the concentration at any given time t. 2

13 The dissolution of solids in liquids can be seen as two consecutive stages. During the first stage, solid molecules are removed from the surface of the solid through an interface reaction (a reaction between the solid and liquid molecules in contact with each other at the solid-liquid interface). During the second stage these "loosened" molecules are transported from the surface of the solid to the surrounding medium under the influence of diffusion or convection (Abdou, 1989:11). Factors influencing the dissolution rate of orally administered drugs can be deduced from the dissolution equation. The most important factor, for the purpose of this study is the effective drug surface area, which in turn depends on the particle size, disintegration and deaggregation, and the effect of manufacturing procedures. Another factor is the solubility of the drug in the diffusion layer, which depends on ph effects and salt formation. While tablet disintegration is frequently a necessary prerequisite for drug dissolution, it in no manner assures that a drug will dissolve. However, dissolution cannot effectively take place without prior disintegration (Kanig & Rudnic, 1984:51 ). Therefore, disintegration can to some extent govern drug efficiency, especially in the case of poorly water-soluble drugs. Formulation and processing factors influencing drug release from tablets include manufacturing procedures, type of filler/binder used, type of disintegrant used, lubricant, hygroscopicity, solubility, compression force and mixing conditions. 1.3 DIRECT COMPRESSION: A SIGNIFICANT ADVANCE IN TABLET MANUFACTURING Wet granulation is the oldest and best documented method of tablet manufacture and involves the manufacturing of granules in order to provide mixtures with tabletable properties. These properties include binding forces, uniform particle size and good flow properties to ensure effective compaction. The term direct compression is used to define the process by which tablets are compressed directly from powder blends of the 3

14 active ingredient and suitable excipients (including fillers, disintegrants and lubricants), that will flow uniformly into a die cavity and form into a firm compact. The advent of direct compression was made possible by the commercial availability of directly compressible vehicles that possess both fluidity and compressibility. The simplicity of the direct-compression process is obvious. It requires, however, a new and critical approach to the selection of raw materials, flow properties of powder blends, and effects of formulation variables on compressibility. The properties of each and every raw material and the process by which these materials are blended become extremely critical to the compression stage of tableting. Direct compression is a unique manufacturing process requiring new approaches to excipient selection, blending and compressibility, and there are few drugs that cannot be directly compressed (Shangraw, 1989:196). The most obvious advantage of direct compression is economy. Savings can occur in a number of areas, including reduced processing time and thus reduced labour costs, fewer manufacturing steps and pieces of equipment, less process validation, and a lower consumption of power. The most significant advantage in terms of tablet quality is that of processing without the need for moisture and heat which is inherent in most wet granulation procedures, and the avoidance of high compaction pressures involved in producing tablets by slugging or roll compaction. The unnecessary exposure of a drug to moisture and heat can never be justified; it cannot be beneficial and may certainly be detrimental. Probably one of the least recognised advantages is the optimisation of tablet disintegration, in which each primary drug particle is liberated from the tablet mass and is available for dissolution. The granulation process, wherein small drug particles with a large surface area are "glued" into larger agglomerates, is in direct opposition to the principle of increased surface area for rapid drug dissolution. Disintegrating agents, such as starch, added prior to wet granulation are known to be less effective than those added just prior to compression. In direct compression all of the disintegrant is able to perform optimally, and when properly formulated, tablets made by direct compression should disintegrate rapidly to the primary state. However, it is important that sufficient disintegrant be used to separate each drug particle if ideal dissolution is to occur {Shangraw, 1989: 198). 4

15 Although there are many advantages to direct compression, there are also some restrictions. Many active ingredients are not compressible in either their crystalline or their amorphous forms. Thus, in choosing a vehicle it is necessary to consider the dilution potential of the major filler (i.e. the proportion of active ingredient that can be compressed into an acceptable compact utilising that filler). Fillers range from highly compressible materials such as microcrystalline cellulose to substances that have very low dilution capacity such as spray-dried lactose. It is not possible to give specific values for each filler because the dilution capacity depends on the properties of the drug itself. Another concern in direct compression is content uniformity. The granulation process locks active ingredients into place and, provided the powders are intimately dispersed before granulation and no drying-initiated unblending occurs after wetting, this can be advantageous. Direct compression blends are subject to unblending in postblending handling steps. The lack of moisture in the blends may give rise to static charges thc:it can lead to unblending. Differences in particle size or density between drug and excipient particles may also lead to unblending in the tablet press (Shangraw, 1989:200). To prevent particle segregation due to size differences in the mixture component, the filler must have a fairly uniform particle size and particle shape. Thus, wet granulation ensures uniform mixture content, but with direct compression the uniformity of the mixture depends largely on the mixing process. Since the filler constitutes the largest percentage of the mixture, the tableting properties are largely determined by the properties of the filler. With wet granulation a binding agent is always added, but it is often not necessary to add a binding agent to directly compressible mixtures. Some directly compressible fillers possess binding properties such as cohesive forces or hydrogen bonding (Battista & Smith, 1962:21; Fox et al., 1963:260). In turn, these bindings affect the crushing strength, friability and disintegration of the tablets. A binding agent has to be added to formulations where the filler does not possess adequate binding properties. The solubility and hygroscopicity of the filler will determine the necessity for the incorporation of other excipients such as disintegrants. The aim of formulation must be to produce tablets with fast and effective drug release and dissolution. It is important to note that with direct compression, higher compression pressures are used than with wet granulation. These higher compression pressures are necessary to form 'strong' tablets, in other words, to produce and enhance bonds 5

16 between individual particles. This can lead to capping, long disintegration times and slow dissolution. Therefore the choice of excipients (especially the filler) is very important in direct compression. 1.4 EFFECT OF FORMULATION VARIABLES AND PROCESSING FACTORS ON PROPERTIES OF AND DRUG RELEASE FROM DIRECTLY COMPRESSED TABLETS The factors influencing tablet properties and drug release and dissolution profiles from directly compressed tablets can be classified into two groups, namely: formulation variables and processing variables. The following section contains a brief discussion of the various factors, emphasising the interdependency of these factors and the importance of each in order to assure a quality product (in terms of physical properties) and effective drug release and dissolution (both in terms of rate and extent) necessary for optimum drug efficiency. The discussion also focuses (with motivation) on the excipients and processes employed in this particular study. In figure 1.2 the factors affecting drug release and dissolution are shown. 6

17 Drug & filler solubility Formulation solubility DRUG RELEASE Rate of disintegration Mechanical strength of tablets Mixing time & intensity Compression properties Properties of binder filler properties (bonding mechanism) Compression force Lubricant effect Mixing time & intensity Access of liquid to particles Mechanism of action Disintegrant efficiency Type/concentration of disintegrant Porosity of tablet-matrix structure Compression force Filler properties Solubility of formulation Filler & drug solubility Hydrophobicity of tablet Type/concentration of lubricant Mixing time & intensity Figure 1.2: Factors influencing drug release and dissolution from an intact tablet 7

18 1.4.1 PROPERTIES OF SOME POPULAR EXCIPIENTS USED IN DIRECT COMPRESSION FORMULATIONS AND THEIR EFFECT ON TABLET CHARACTERISTICS AND DRUG RELEASE The filler is the most important excipient in direct compression, since it is the filler that determines the tableting properties of the mixture, and it is not possible to directly compress only the active ingredient. The filler is the only excipient without which direct compression is not possible. Other excipients sometimes used in direct compression, depending on the properties of the filler, are binders, disintegrants and lubricants. The binder provides binding properties to the tablets. Binders can increase the mechanical strength of a tablet, and therefore retard disintegration and dissolution. Then it becomes important to add the right disintegrant in the right concentration to the formulation to ensure that the tablet can overcome the bonding forces between individual particles. Lubricants are added to minimise adhesion forces that develop between the tablet and the die wall. Some fillers possess adequate bonding, disintegrating or lubrication properties, and it is not necessary to include any of these excipients to the formulation. Some of the traditional excipients used in tablet formulations, like the starches, gave way to new and better excipients with better flow properties and better compressibility. The ideal excipient for direct compression tableting should be free-flowing, inert with respect to chemical, physical and physiological reactivity, relatively inexpensive, and compressible into tablets which exhibit excellent hardness, friability, disintegration time and dissolution rate of the active ingredient (Bolhuis & Lerk, 1973:471 ). Its particle size distribution must match with a wide range of drugs, it must have a good pressurehardness profile and capable of handling without a decrease in compressibility or fluidity (Shangraw, 1989:203). It is therefore important to give careful consideration to the choice of the excipients used in a formulation Fillers Since the active ingredient usually constitutes such a small percentage of the total tablet weight, it is impossible to compress tablets containing only the active ingredient. Therefore inert substances, namely fillers, are added to reach a tabletable weight. Other reasons for including fillers in tablet formulations are to: 8

19 1. provide tablets with certain physical characteristics, 2. improve powder flow, 3. make direct compression possible, 4. improve tablet disintegration and 5. provide binding properties. There are many types of fillers/binders available for direct compression as shown in table 1.1. Table 1.1: Fillers for direct compression (Bolhuis & Lerk, 1973: ). Filler a-lactose monohydrate a-lactose monohydrate/pvp Microcrystalline cellulose Microfine cellulose Dicalcium phosphate dihydrate Directly compressible starch Sucrose Trade name Tablettose Ludipress Avicel PH Elcema Emcompress STA-Rx 1500, Emdex. Celutab Sugartab, Di-Pac, Nu-Tab The most frequently used fillers include the lactose-types, microcrystalline cellulose and dicalcium phosphate dihydrate. Lactose is probably the oldest filler/binder in tableting. It has no disintegrant properties and because lactose lacks essential fluidity and compressibility in its regular form, common lactose cannot be used in direct compression of tablets without modification. Riepma et al. (1992: 123) showed differences in consolidation and compaction between the granular lactose types, i.e. roller-dried 13- lactose and anhydrous a-lactose, and the non-granular lactose types, namely, crystalline 13-lactose and a-lactose monohydrate. a-lactose monohydrate Ludipress contains a-lactose-monohydrate as filler/binder. The other components, povidone (Kollidon 30) and crospovidone (Kollidon CL), increase compactibility and provide a certain swelling activity (Schmidt & Rubensdorfer, 1994:2901 ). Due to its 9

20 composition, Ludipress as a single adjuvant can substitute various tablet ingredients and acts as a multipurpose excipient for direct compression (Schmidt & Rubensdorfer 1994:2925). Ludipress granules have a spherical shape, which explains the good flowability of this excipient. The single crystals are held together by amorphous components. These are mainly povidone, crospovidone and amorphous lactose ("lactose glass", which is generated during the production process). As lactose glass undergoes plastic deformation during compaction, it increases the binding capacity of lactose. Therefore, in order to achieve a high dilution potential, a lactose based tableting excipient should contain a high amount of lactose glass (Schmidt & Rubensdorfer, 1994:2905). A disintegration or dissolution optimum at a certain compaction load of a lactose based granule containing povidone and crospovidone has been reported earlier by Khan and Rooke (1976:633). Disintegration efficiency increases progressively with increasing pressure, until an optimum pressure is reached. This phenomenon can be explained by the packing density of the tablet. At 75.1 MPa, packing of the tablet is loose. Intact lactose crystals and amorphous constituents can be detected clearly. During water uptake the swelling of the crospovidone (a cross-linked insoluble polymer) will lead to tablet disintegration. Due to the loose packing of the tablet, a certain amount of swelling volume will vanish into the numerous voids of the compact causing prolonged disintegration. By increasing the compaction load up to 100 MPa, plastic deformation of the amorphous constituents occurs, providing optimal tablet properties. The single crystals are "glued" together, leading to a significant reduction in friability. Due to the augmented packed density, the interparticulate volume decreases, thus enabling the crospovidone in Ludipress to establish its swelling activity properly. A further increase of the compaction pressure causes a more brittle fracture of the lactose crystals and a strong decrease in tablet porosity. Consequently water uptake is impeded and disintegration time increases (Schmidt & Rubensdorfer, 1994:2913). 10

21 Tablettose is soluble in water and consists of a free-flowing a-lactose-monohydrate granule instead of the fine lactose used in the production of Ludipress. Ludipress also contains an additional binder (povidone) and disintegrant (crospovidone), and is therefore more efficient than Tablettose. Ludipress produces harder tablets compared to tablets prepared from Tablettose (Schmidt & Rubensdorfer, 1994:2907). Anhydrous lactose Anhydrous lactose possesses excellent flow and compression properties. It produced highly elegant tablets on a high-speed rotary tablet machine. Both placebo and active tablets were excellent as shown by the elegance, small tablet weight variation, uniform distribution of the active ingredient, fast disintegration and dissolution rates, good hardness, low friability, and lack of binding, sticking, and capping (Batuyios, 1966:728). Lerk et al. (1974:951) found that lactose could not be tableted without lubricant because of high ejection forces, resulting in crushing of the tablets during ejection, and because of sticking to the punches and die. Direct compression was consequently in all cases performed with 0.5% magnesium stearate. Lactose anhydrous exhibits a flowability which was just sufficient for direct compression and produced strong compacts. Combination of anhydrous lactose with extra fine crystalline (EFK) lactose or Avicel PH- 101, produced products with good flowability an'd compacts with good strength, and a somewhat increased disintegration time. The lactose anhydrous-avicel compacts showed no significant change in crushing strength with an increase in the amount of Avicel. 11

22 Combination of extra fine crystalline lactose with Avicel, however, produced a sharp decrease in disintegration time and an increase in crushing strength with an increase in percentage of Avicel. The remarkable difference in effect of Avicel on the disintegration behaviour of Avicel -lactose anhydrous compacts compared with Avicel lactose EFK compacts can most probably be attributed to the pronounced difference in dissolution time between lactose anhydrous and lactose EFK (Lerk et al., 1974:955). Both crushing strength and disintegration time are strongly dependent on the type of the lactose used. The incorporation of 0.5% magnesium stearate caused a decrease in crushing strength and an increase in disintegration time for all lactose tablets. The largest increase in disintegration time was found for tablets containing a-lactose m,onohydrate (Van Kamp et al., 1986:221). Van Kamp et al. (1986:221) studied the effect of the nature of the lactose and the presence of the lubricant on the dissolution rate of caffeine from tablets. For unlubricated tablets, the dissolution rate of caffeine strongly depends on the type of lactose used and was, in comparison with the other types, lowest for anhydrous a lactose. The presence of magnesium stearate decreased the dissolution rate of caffeine for all the tablets investigated, but the magnitude of the effect was dependent on the lactose used. Dicalcium phosphate dihydrate Emcompress is a free-flowing form of dicalcium phosphate dihydrate and is insoluble in water. It offers a fairly good pressure-hardness profile, possesses satisfactory flowability and has a capacity potential for the incorporation of non-compressible material to the extent of about 40%. The non-hygroscopicity of dicalcium phosphate dihydrate is outstanding. It should be noted that dicalcium phosphate dihydrate is on the alkaline side, with a ph of 7.0 to 7.3, which precludes its use with active ingredients that are extremely sensitive to even minimal amounts of alkalinity (Mendell, 1972:43). 12

23 Although Emcompress has a good compressibility, it has no disintegrating action. It is therefore necessary to include an excipient with disintegrating properties, like Avicel PH-102, in the formulation (Lerk et al., 1974:946). Microcrystalline cellulose Along with the characteristic inertness and absorbent properties exhibited by most cellulose compounds, Avicel, which consists of microcrystalline cellulose, is nonfibrous, free-flowing and possesses an extremely high surface area. Battista and Smith (1962:21) found that this microcrystalline "flour'' could be compressed into very hard tablets with normal tableting equipment. Such tablets disintegrated immediately when placed in water as a result of the destruction of the cohesive bonding forces holding the microcrystalline particles together, Thus, microcrystalline cellulose has the ability to form extremely hard tablets that are not friable and yet possess unusually short disintegration times. Avicel can be used as a filler, binder, disintegrating agent and lubricant in tablet formulations (Fox et al., 1963:161). Preliminary investigation showed that microcrystalline cellulose had good flow properties in spite of its extremely small particle size, and that in high concentrations it acted as its own lubricant. Although in high concentrations it appears to be nonadherent in respect to the punches and die, it cannot be classified as a lubricant. The reason for this, is that when the concentration is reduced below the point where other constituents have significant wall contact, the addition of a true lubricant is necessary (Fox et al., 1963:260). Fox et al. (1963:258) predicted that as long as the concentration of microcrystalline cellulose is kept above 60 to 70%, direct compression of many formulations without the inclusion of any additives would be possible. The concentration of microcrystalline cellulose might even be reduced further if crystalline active ingredients or diluents are used. Another major advantage of microcrystalline cellulose appears to be its ability to act as a dry binder. Many chemical substances that are impossible to compress alone 13

24 or in reasonable dilution with other fillers may be tableted with microcrystalline cellulose (Fox et al., 1963:260). Disintegration action of microcrystalline cellulose The disintegration of microcrystalline cellulose tablets has been attributed to the entrance of water into the tablet matrix by means of capillary pores and the subsequent breaking of the hydrogen bonding between adjacent bundles of cellulose microcrystals (Fox et al., 1963:260). When compression pressure is increased, capillary porosity becomes smaller and disintegration time increases. Upon pressure the matchstick-like bundles of microcrystals (figure1.3) appear to line themselves up into layers. This arrangement decreases the bond distance between particles and further increases the inter-particulate forces, and thus reduces the entrance of water into the tablet matrix with an increase in disintegration time. Avicel might prove useful in specific formulations solely on the basis of its disintegrating ability. When it is employed as a filler/binder in concentrations above 20 per cent, microcrystalline cellulose gives extraordinary disintegration results. -...~ Figure 1.3: Matchstick-like bundles of microcrystalline cellulose microcrystals (Fox et al., 1963:163). In high concentrations, disintegration is so rapid that difficulty in swallowing tablets results from break-up in the mouth. Another striking effect is a sticking of the tablets to 14

25 the tongue or oral mucosa. The saliva is apparently absorbed into the capillary spaces, dehydrating the moist surface, and causing adhesion (Fox et al., 1963:260). Characteristics of different A vie.el grades PH means the excipient is suitable for dry applications like direct compression. Avicel PH grades differ from each other by their particle size, particle shape and moisture content. Doelker et al. (1995: ) studied the characteristics of different Avicel PH grades (Table 1.2). This evaluation should not be put in parallel with other published evaluations where the operating conditions were generally different. Table 1.2: Evaluation of the basic and tableting properties of the Avicel PH grades relatively to Avicel PH-101 (Doelker et al., 1995:659). (+,++better; =not significantly different; -, -- worse) Material Hausner Compac- Sensitivity to Regularity of Disintegraratio 1 tibility2 lubricant3 weight tion 4 -- Avicel PH Avicel PH- 103 = = - = Avicel PH- = = Avicel PH- + = Avicel PH- ++ = Compressibil1ty on tappmg, Based on the compact crushmg strength, Strength reduction ratio on adding 0. 5% magnesium stearate; 4 Both with or without disks. = = = = The large-particle-size-grade PH-200 display a compactibility close to that of almost all the other Avicel PH grades, but the highest susceptibility to magnesium stearate. The larger the particles in the powder mixture, the larger are the shearing forces during mixing. Shearing forces form a magnesium stearate film on the particles, producing weaker tablets when compressed (Doelker et al., 1995:659). 15

26 Tablets made of Avicel PH-200 exhibit the lowest weight variability because of its good flowability. The disintegration properties of the tablets are similar to those made of other PH grades, however, the higher the amounts of PH-200 in the mixture, the faster the tablets disintegrate. The shortest disintegration time of tablets is achieved when only Avicel PH-200 is used. Avicel PH-200 showed certain advantages when compared to the other PH grades and were therefore chosen to evaluate in this study: It is the only free-flowing material in the group with the highest flow rate at 13.3 g.sec 1; It has the highest true and bulk density (1.54 and g.cm 3 respectively); It produces tablets with the best tablet weight reproducibility, lowest weight variation and lowest variation in tablet thickness; Relatively fast disintegration times (Doelker et al., 1995: ). When compressed, the weakest tablets are formed of Avicel PH-200, but they still have a crushing st~ength of over 135N at moderate compression forces Binders Binders supply or increase binding forces between particles, to ensure that particles stay together. Many fillers also possess binding properties and will therefore be referred to as fillers/binders. Where the filler does not possess binding properties, a binding agent has to be added to the formulation in order to compress tablets from the mixture. Kollidon 30 (povidone, po/yvidone) The soluble grades of Kollidon possess a number of very useful properties for which they are widely used in pharmaceuticals. Because of these properties, the products can perform different functions in different dosage forms. General properties of the soluble Kollidon grades are: solubility in all conventional solvents, 16

27 adhesive and binding power, film formation, affinity to hydrophilic and hydrophobic surfaces, ability to form complexes, availability in different molecular weights and thickening properties (Buhler, 1993:70). Their adhesive and binding power is particularly important in tableting. Kollidon is available in grades of different average molecular weight (indicated by the K-value in the trade name). With increasing molecular weight, the dissolution rate of the soluble Kollidon grades decreases, while the adhesive power, the viscosity and often also the ability to form complexes increase. This dependence of the properties on the molecular weight makes it possible to provide the optimum grade for each dosage form or formulation and to achieve the optimum effect (Buhler, 1993:72). The main area of application of. Kollidon 25, 30 and 90 is as binder for tablets. Kollidon 90 is a stronger binder than Kollidon 25 or 30. Kollidon 30 was chosen for the purpose of this study, as it has intermediate properties. Kollidon VA 64 (copo/yvidone) In contrast to the soluble grades of Kollidon described above, the number, 64 in the trade name, Kollidon VA 64, is not a K-value but the mass ratio of the two monomers, vinylpyrrolidone and vinyl acetate. Kollidon VA 64 is however, also water-soluble. The K-value of Kollidon VA 64 is of the same order of magnitude as that of Kollidon 30 and is also used as a measure of the molecular weight(buhler, 1993: 191 ). The main area of application of Kollidon VA 64 is as a binder in tablets and granules, regardless if they are manufactured by wet granulation or direct compression, as it is equally as effective in all three cases. The advantage of Kollidon VA 64 over Kollidon 25 and Kollidon 30 in solid dosage forms lies mainly in its lower hygroscopicity. An important property of Kollidon VA 64, in its use as a binder for tablets, is its plasticity, a 17

28 property that Kollidon 30 does not possess. This property gives granules and mixtures that are less susceptible to capping during compression, and tablets that are less brittle. The tablets also have less tendency to stick to the punches when tableting machines are operated under humid conditions (Buhler, 1993:214). Both Kollidon 30 and Kollidon VA 64 are used in concentrations of 2-5% Disintegrants For tablets containing sparingly water-soluble drugs, it is often desirable that the start of dissolution is not delayed by a prolonged lag time due to slow or poor wetting of the tablet surface and slow or poor liquid penetration into the tablet matrix, resulting in slow disintegration of the tablets. Hence, disintegrants with a fast action are most useful in tablet formulations of sparingly water-soluble drugs (Gissinger & Stamm, 1980: 189). A wide range of materials has been used as disintegrants in tablet formulations (Lowenthal, 1972:1696). Of these, the starches are the most well-known and widely used, but they have certain shortcomings in direct compression, including: relatively high concentrations needed for optimum disintegrant efficiency, poor disintegration in insoluble formulations, suspect to high compression forces which decrease their efficiency, decreased disintegration efficiency in the presence of hydrophobic lubricants, and poor compr~ssion properties (Marais, 2000:64). The use of the traditional starches in directly compressed formulations presented problems in terms of the high concentrations needed for optimum disintegration. These materials cause significant weight variations in directly compressed formulations. This led to the search for new, more effective disintegrants. The result of this research was the marketing of a group of materials, called the superdisintegrants, which included sodium starch glycolate (Explotab and Primojel ), croscarmellose sodium (Ac-Di-Sol ) and crospovidone (Kollidon CL). 18